Cutting-Edge Leukemia Research at Children’s

from Practice Update, Summer 2007

Roger Giller, MD, co-chair, Center for Cancer and Blood Disorders,clinical director, Bone Marrow Transplant Program, The Children’s Hospital,Professor, Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplant, UCDHSC

Douglas Graham, MD, PhD, scientific director, Experimental Therapeutics Program, Assistant Professor, Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplant, UCDHSC

Approximately 12,400 children and adolescents under the age of 20 are diagnosed with cancer in the United States annually, with Leukemia being the most common cancer diagnosis. Acute Lymphoblastic Leukemia (ALL) accounts for one-fourth of all childhood cancers, and approximately 85 percent of cases of childhood leukemia. The current five-year survival rate for patients with ALL is approximately 80 percent, a rate that has steadily increased over the last three decades through optimizing chemotherapy combinations. In a similar manner, the cure rate for Acute Myeloid Leukemia (AML), the second most common form of leukemia in the pediatric population, has improved, and now about half of all children and adolescents with AML achieve long-term survival.

Despite the success in treating the majority of pediatric leukemia patients, there are still significant improvements to be made in pediatric leukemia treatment regimens, including the need to identify treatments with less toxicity and fewer side effects. In addition, better treatments are needed for children with leukemia, who have poor prognoses, such as infants, children who relapse, and those with specific high risk genetic mutations in their leukemia cells.

At the Center for Cancer and Blood Disorders at The Children’s Hospital, a group of physicians and scientists skilled in basic research and clinical trial design and oversight are working to improve treatments and outcomes for children, adolescents and young adults with leukemia. Research and treatment involves numerous groups and programs within the Center, including General Oncology, Bone Marrow Transplant (BMT) and the Experimental Therapeutics Program. The Center has gained international recognition recently through the following accomplishments:

• Characterization of Mer, a leukemia-promoting oncogene, by using molecular genetic techniques and a mouse model of childhood ALL.
• Discovery of promising anti-leukemic activity of a new chemotherapy agent, forodesine, in a phase I (initial pediatric use) clinical trial.
• Successful use of cord blood and other forms of hematopoietic stem cell transplantation in ALL and AML cases with poor prognoses.
• Leadership of three national multicenter clinical trials in ALL.
• Leadership in national studies of pediatric leukemia biology.

Basic and translational leukemia research doctors include Doug Graham, MD, PhD; Deb DeRyckere, PhD; Lia Gore, MD; Amy Keating, MD and James DeGregori, PhD. Leukemia clinical research doctors include Roger Giller, MD; Ralph Quinones, MD and Lia Gore, MD. Drs. Graham and Keating study abnormal signaling pathways in cancer cells. Drs. DeRyckere and Gore investigate efficacy of potential new drugs in preclinical studies. Dr. DeGregori researches how leukemia cells gain a competitive advantage in the bone marrow.

BMT team, under the guidance of clinical director Dr. Roger Giller, continues to advance the use of bone marrow transplant to treat resistant forms of leukemia. Drs. Roger Giller and Ralph Quinones design and carry out clinical trials using hematopoietic stem cell transplantation for treatment of chemotherapy resistant forms of pediatric leukemia. They focus on optimal drug and radiation treatment strategies to circumvent prior chemotherapy resistance. Drs. Giller and Quinones also investigate blood-forming stem cells capable of mediating an anti-leukemic impact through immune mechanisms.

In addition to his participation in the BMT program, Dr. Quinones researches the use of unrelated cord blood for hematopoietic stem cell transplants for children with refractory leukemia who do not have well matched family donors. Dr. Quinones is the co-founder and medical director of the University of Colorado Cord Blood Bank (UCCBB). UCCBB was recently chosen as one of the six congressionally funded cord blood banks to lead the effort to increase the national inventory of cord blood for hematopoietic stem cell transplants for patients of all ages with refractory leukemia.

Specialists in clinical trial design also include Dr. Lia Gore, who is actively involved in both the Children’s Oncology Group (COG) ALL trials and the Pediatric Oncology Experimental Therapeutics Investigation Consortium (POETIC) national phase I leukemia trials. Recently, Dr. Gore piloted a new clinical drug trial, the first of its kind in the world, to treat pediatric patients with a rare type of leukemia. Of the five children in the world enrolled in the trial, two are at Children’s. The protocol uses the drug forodesine, which is used to treat leukemia and lymphoma in adults, to treat B-cell lineage leukemia in children. Dr. Gore explains, “We are a comprehensive cancer center working on the development of the next generation of leukemia trials and new approaches to cancer therapy and pediatric cancer research.”

Doug Graham, MD, PhD, an expert in T cell ALL, led clinical trial design for a Children’s Oncology Group T cell leukemia trial, which will enroll patients nationwide over the next five years. This leukemia research seeks to identify abnormal cancer proteins, which can be targeted with new drugs, leading to long term cures with minimal side effects of therapy.

Kelly Maloney, MD currently heads up the national Children’s Oncology Group’s phase III standard risk ALL clinical trial, the largest active pediatric cancer trial in the country.

Pediatric researchers at Children’s capitalize upon the affiliation of The Children’s Hospital with the University of Colorado at Denver and Health Sciences Center to improve outcomes for young leukemia patients. A working relationship with colleagues at the University of Colorado Cancer Center, who specialize in adult oncology and bone marrow transplant, often provides insight into pediatric cancer research. New laboratory space available through the construction of one of the largest research complexes in the country on the University’s new medical campus opens doors to expanded research opportunities. As The Children’s Hospital prepares to move to its new location adjacent to research facilities and medical schools, pediatric researchers will continue to develop treatments to save young lives and improve the quality of life for leukemia patients.